Highlights from Recent Cancer Literature
Journal: Cancer Research (2016)

The authors report a study of 692 patients with metastatic prostate cancer. Whole-exome or directed next-generation sequencing affirmed that 11.8% of men with metastatic prostate cancer had germline mutations in DNA repair genes. There was no clear correlation with patient-related factors, with a slight increase in higher grade cancer at diagnosis. Examining the germline of 499 men with localized prostate cancer, the authors found that 4.6% of the men had mutations in DNA repair genes. This enrichment of germline carriers in metastatic versus localized disease is intriguing. Thus, DNA repair may have metastasis suppressor properties indirectly and/or directly in prostate cancer. These data make a compelling argument that men with metastatic prostate cancer should have both somatic and germline mutation DNA repair gene testing.Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443–53.Focal adhesion kinase 1, a nonreceptor tyrosine kinase, is postulated to play a role in regulating the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). Jiang and colleagues illustrate that FAK1 (PTK2) hyperactivation in pancreatic tumors was associated with extensive collagen deposition and inflammatory cells, but few CD8+ cytotoxic T lymphocytes. FAK inhibition depleted the stromal, along with tumor-infiltrating myeloid-derived suppressor cells, CD206+ tumor-associated macrophages, and CD4+FOXP3+ regulatory T cells. Treated tumor cells showed decreased p-STAT3, and suppressed progression was observed in mouse models. FAK inhibition potentiated the efficacy of chemotherapy and immunotherapy in previously resistant PDAC models by altering the fibrotic and immunosuppressive TME. These findings have immediate translational relevance and can be extended to elucidate the role of FAK signaling in other tumor types.Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nature Med 2016;22:851–60.Xie and colleagues used a NOTCH reporter system dependent on recombining binding protein suppressor of hairless (RBPJ) binding sites, revealing strikingly that brain tumor-initiating cells (BTIC) from several patient-derived glioblastoma lines were NOTCH insensitive, but required RBPJ for growth and self-renewal in vitro and in vivo. They showed that RBPJ binds to CDK9, promoting transcriptional elongation. By H3K27ac ChIP-seq, RBPJ acted as a transcriptional enhancer and shared bound promoters with CDK9. Two CDK9 inhibitors, dinaciclib and LY2857785, showed significant activity against BTICs. Because MYC binds to the RBPJ promoter, they treated BTICs with JQ1, resulting in reduced expression of MYC and RBPJ, and decreased growth. Although NOTCH signaling may not be critical for BTIC growth and self-renewal, combining inhibitors against CDK9 and BET bromodomains represents a therapeutic strategy against glioblastoma BTICs.Xie Q, Wu Q, Kim L, Miller TE, Liau BB, Mack SC, et al. RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. Journal of Clin Invest 2016;126:2757–72.Reactive oxygen species (ROS) limit both life-span and antitumor functions of T cells. Because TP53 is a redox active transcription factor that regulates cellular ROS generation, Banerjee and colleagues determined how TP53 influences persistence and function of tumor-reactive T cells. In T cells from transgenic h3T-TCR mice (tyrosinase epitope-reactive T cells), deletion of Trp53 led to enhanced glycolysis, increased proliferation, IFNγ secretion, cytolytic capacity, expression of a stemness gene signature, and decreased TGFβ signaling. Subcutaneous melanoma tumors showed improvement after adoptive transfer of Trp53-KO T cells. Treatment of human TCR-transduced T cells with pharmacological inhibitors of TP53 also enhanced T-cell effector function and improved persistence. Thus, TP53 plays a key role in regulating tumor-reactive T-cell responses. These findings have potential translational significance in adoptive T-cell therapy.Banerjee A, Thyagarajan K, Chatterjee S, Chakraborty P, Kesarwani P, Soloshchenko M, et al. Lack of p53 augments anti-tumor functions in cytolytic T cells. Cancer Research; Published OnlineFirst July 27, 2016; doi: 10.1158/0008-5472.CAN-15-1798.Gao and colleagues identified an evolutionarily conserved atypical tetraspanin TM4SF1 as a strong mediator of metastatic reactivation. Known connections of TM4SF1 with the collagen receptor tyrosine kinase DDR1 suggested a link. They found that collagen was abundantly secreted by breast cancer cells in vitro and drove proliferation of 3D spheroids. Furthermore, breast carcinoma metastatic nodes demonstrated close contact between collagen and cancer cells. Mechanistically, TM4SF1 enabled DDR1 clustering in response to collagen, coupling it to the cortical adaptor syntenin 2 and to PKCα. Independently of DDR1 tyrosine kinase activity, PKCα phosphorylates and activates JAK2, leading to activation of STAT3, induction of SOX2 and NANOG expression, and the maintenance of cancer stem cell traits. Thus, contact with collagen I triggers metastatic reactivation of breast cancer via this pathway in multiple organs.Gao H, Chakraborty G, Zhang Z, Akalay I, Gadiya M, Gao Y, et al. Multi-organ site metastatic reactivation mediated by non-canonical discoidin domain receptor 1 signaling. Cell 2016;166:47–62.Circulating tumor cells (CTC) and CTC clusters shed from tumors represent “liquid biopsies” for early diagnosis, serial assessment of treatment response, and even elucidating mechanisms of acquired resistance in response therapy. Studying CTC clusters from patients with colorectal cancer, Cima and colleagues detected cells with an endothelial marker phenotype. These circulating endothelial clusters were not malignant but represented clusters of tumor-derived, nonproliferating endothelial cells resembling tumor vasculature. These endothelial cell clusters were found in 87% of patients with colorectal cancer. They did not associate with any known patient or tumor-related factors, but did correlate inversely with treatments. These new findings suggest patients with colorectal cancer harbor a distinct population of nonproliferating endothelial cell clusters circulating in the blood and add to the growing taxonomy of tumor-derived circulating cells in the pathologic state.Cima I, Kong SL, Sengupta D, Tan IB, Phyo WM, Lee D, et al. Tumor-derived circulating endothelial cell clusters in colorectal cancer. Sci Transl Med 2016;8:345ra89. doi: 10.1126/scitranslmed.aad7369.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.